Project Summary: The Women's Health Initiative study has shown an increase in cardiac risk among the postmenopausal women who received daily oral conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) treatment, but not among those who received CEE alone. Peripheral blood markers of inflammation, specifically C-reactive protein (CRP) and interleukin-6 (IL-6), have been increasingly recognized as predictors of cardiac events and have led to new insights about pathophysiological mechanisms for these events. Previous studies suggest that CEE with a progestin treatment differs from CEE alone treatment in its effects on various biological risk factors for cardiac events, including inflammation markers and their association with fibrinogen level. However, research to date has provided only indirect evidence linking progestin to coronary heart disease and has not accounted for the post-treatment variability in serum levels of progestins resulting from medication compliance or differences in medication absorption and metabolism. In this proposed study, we will use data from 459 participants from the active treatment arms of the Postmenopausal Estrogen Progestin Intervention (PEPI) randomized clinical trial to assess how serum levels of progestins are related to inflammatory marker levels and influence the associations between inflammation and other cardiac risk factors. Serum MPA and progesterone levels, which are being measured currently on longitudinal stored serum samples, will be linked to extensive sociodemographic, lifestyle, clinical information, and biomarkers already collected or measured in the trial. This proposed study would be the first one to directly examine the relations between progestin levels and predictors for coronary heart disease. The findings may also lead to new independently-funded studies to evaluate the relations between serum progestin levels and other risk factors for atherosclerosis, such as endothelial dysfunction, oxidized LDL cholesterol, or complement activation. Relevance: The findings from this study may provide substantial insight into the role progestins play in the development and progression of cardiovascular diseases and help to understand why hormone use is associated with increased cardiac events in postmenopausal women. [unreadable] [unreadable] [unreadable]